Altered oncomodules underlie chromatin regulatory factors driver mutations
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Joan Frigola1, Ane Iturbide2, Nuria Lopez-Bigas1,3, Sandra Peiro2, Abel Gonzalez-Perez1
1Research Program on Biomedical Informatics, IMIM Hospital del Mar Medical Research Institute and Universitat Pompeu Fabra, 08003 Barcelona, Catalonia, Spain
2Programa de Recerca en Càncer, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), 08003 Barcelona, Spain
3Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain
Abel Gonzalez-Perez, email: [email protected]
Keywords: chromatin regulatory factors, CRFs oncogenic modules, indirect targeted therapeutic strategies, CRFs Oncomodules Discovery, oncogenic modules scoring system
Received: September 29, 2015 Accepted: March 31, 2016 Published: April 15, 2016
Chromatin regulatory factors (CRFs), are known to be involved in tumorigenesis in several cancer types. Nevertheless, the molecular mechanisms through which driver alterations of CRFs cause tumorigenesis remain unknown. Here, we developed a CRFs Oncomodules Discovery approach, which mines several sources of cancer genomics and perturbaomics data. The approach prioritizes sets of genes significantly miss-regulated in primary tumors (oncomodules) bearing mutations of driver CRFs. We applied the approach to eleven TCGA tumor cohorts and uncovered oncomodules potentially associated to mutations of five driver CRFs in three cancer types. Our results revealed, for example, the potential involvement of the mTOR pathway in the development of tumors with loss-of-function mutations of MLL2 in head and neck squamous cell carcinomas. The experimental validation that MLL2 loss-of-function increases the sensitivity of cancer cell lines to mTOR inhibition lends further support to the validity of our approach. The potential oncogenic modules detected by our approach may guide experiments proposing ways to indirectly target driver mutations of CRFs.
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